Several thousand clinical disorders with documented Mendelian inheritance remain of unknown genetic etiology. Recently, the approximate chromosomal location of the unknown mutant gene at the origin of several clinical diseases has been determined by linkage to newly available DNa markers. Furthermore, knowledge of map location has led to the eventual identification of several mutant genes. Precise mapping information, therefore, can make many important human genes that are defined only by their morbid phenotype accessible to gene cloning. Primary genetic maps of markers adequate for the initial localization of mutant genes are now available for most human chromosomes and should be available soon for the remainder. These widely spaced markers usually provide an average resolution of 10 to 20 cM. Gene identification and cloning, however, require mapping to Within 1 cM in order to confine the search for a mutant gene to a region of only a few metabases, containing only a few candidate genes. Precise mapping of mutant genes by linkage analysis in families require a genetic map of a much greater density. We propose to isolate 2,500 highly polymorphic DNA markers for a specific subset of human chromosomes. Genotypes will be defined for these markers in a set of 59 families with large sibship. We will construct genetic maps of these markers which should afford a resolution of the order of a Centimorgan. We expect these markers will lead to the identification of the genetic mutation involved in numerous classical Mendelian conditions. They may make significant contributions to many ongoing programs aim at mapping, identifying and cloning genes responsible for common disorders such as cancer, cardiovascular disease, or mental illness. Lastly, these markers should serve as primary reference points in the orientation and ordering of extensive cosmid maps prior to large scale genomic sequencing.